5-oxa, 5-thia, 5-aza HmG-CoA reductase inhibitors

ABSTRACT

Novel HMG-CoA reductase inhibitors are useful as antihypercholesterolemic agents and are represented by stuctural formulae (I) and (II): ##STR1## wherein A is O, S(O) n  or N--R 13 .

BACKGROUND OF THE INVENTION

Hypercholesterolemia is known to be one of the prime risk factors forischemic cardiovascular disease, such as arteriosclerosis. Bile acidsequestrants have been used to treat this condition; they seem to bemoderately effective but they must be consumed in large quantities, i.e.several grams at a time and they are not very palatable.

MEVACOR® (lovastatin), now commercially available, is one of a group ofvery active antihyper cholesterolemic agents that functions by limitingcholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. Inaddition to the natural fermentation products, mevastatin andlovastatin, there are a variety of semi-synthetic and totally syntheticanalogs thereof.

The naturally occurring compounds and their semi-synthetic analogs havethe following general structural formulae: ##STR2## wherein: R³ ishydrogen, C₁₋₅ alkyl or C₁₋₅ alkyl substituted with a member of thegroup consisting of phenyl, dimethylamino, or acetylamino; and

⁺ is

⁺ is ##STR3## wherein N is ##STR4## R⁵ is H or OH; M is ##STR5##

R⁶ is hydroqen or hydroxy; R² is hydrogen or methyl; and a, b, c, and drepresent single bonds, one of a, b, c or d represents a double bond, orboth a and c or both b and d represent double bonds provided that when ais a double bond,

N is ##STR6## and when d is a double bond, M is ##STR7##

U.S. patent application Ser. No. 048,136 filed May 15, 1987 discloses6-substituted compounds of the above general formula wherein R⁻ is##STR8## wherein R is ##STR9## and R¹, R⁴, R⁷, R⁸ and R⁹ are broadlydefined organic moieties.

U.S. patent application Ser. No. 142,361 filed Jan. 7, 1988 discloseslovastatin analogs wherein the 6-position is gem-disubstituted:##STR10## R² and R³ are alkyl or substituted alkyl moieties.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds which are useful as HMG-CoAreductase inhibitors. The specific HMG-CoA reductase inhibitors of thisinvention are the compounds represented by structural formulae (I) and(II): ##STR11## wherein: A is O or ##STR12## n is 0 to 2; R₁ is selectedfrom:

(1) C₁₋₁₀ alkyl;

(2) substituted C₁₋₁₀ alkyl in which one or more substituent(s) isselected from

(a) halogen,

(b) hydroxy,

(c) C₁₋₁₀ alkoxy,

(d) C₁₋₅ alkoxycarbonyl,

(e) C₁₋₅ acyloxy,

(f) C₃₋₈ cycloalkyl,

(f) C₃₋₈ cycloalkyl,

(g) phenyl,

(h) substituted phenyl in which the substituents are X and Y,

(i) C₁₋₁₀ alkylS(0)_(n) in which n is 0 to 2,

(j) C₃₋₈ cycloalkylS(0)n,

(k) phenylS(0)n,

(l) substituted phenylS(0)n in which the substituents are X and Y, and

(m) oxo;

(3) C₁₋₁₀ alkoxy;

(4) C₂₋₁₀ alkenyl;

(5) C₃₋₈ cycloalkyl;

(6) substituted C₃₋₈ cycloalkyl in which one substituent is selectedfrom

(a) C₁₋₁₀ alkyl

(b) substituted C₁₋₁₀ alkyl in which the substituent is selected from

(i) halogen,

(ii) hydroxy,

(iii) C₁₋₁₀ alkoxy,

(iv) C₁₋₅ alkoxycarbonyl,

(v) C₁₋₅ acyloxy,

(vi) phenyl,

(vii) substituted phenyl in which the substituents are X and Y

(viii) C₁₋₁₀ alkylS(O)n,

(ix) C₃₋₈ cycloalkylS(O)n,

(x) phenylS(O)n,

(xi) substituted phenylS(O)n in which the substituents are X and Y, and

(xii) oxo,

(c) C₁₋₁₀ alkylS(O)n,

(d) C₃₋₈ cycloalkylS(O)n,

(e) phenylS(O)n,

(f) substituted phenylS(O)n in which the substituents are X and Y,

(g) halogen,

(h) hydroxy,

(i) C₁₋₁₀ alkoxy,

(j) C₁₋₅ alkoxycarbonyl,

(k) C₁₋₅ acyloxy,

(l) phenyl, and

(m) substituted phenyl in which the substituents are X and Y;

(7) phenyl;

(8) substituted phenyl in which the substituents are X and Y;

(9) amino;

(10) C₁₋₅ alkylamino;

(11) di(C₁₋₅ alkyl)amino;

(12) phenylamino;

(13) substituted phenylamino in which the substituents are X and Y;

(14) phenyl C₁₋₁₀ alkylamino;

(15) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are Xand Y;

(16) a member selected from

(a) piperidinyl,

(b) pyrrolidinyl,

(c) piperazinyl,

(d) morpholinyl, and

(e) thiomorpholinyl; and

(17) R⁵ S in which R⁵ is selected from

(a) C₁₋₁₀ alkyl,

(b) phenyl, and

(c) substituted phenyl in which the substituents are X and Y;

R² and R³ are independently selected from:

(1) hydrogen;

(2) C₁₋₁₀ alkyl; and

(3) substituted C₁₋₁₀ alkyl in which one or more substituents isselected from

(a) halogen,

(b) hydroxy,

(c) C₁₋₁₀ alkoxy,

(d) C₁₋₅ alkoxycarbonyl,

(e) C₁₋₅ alkylacyloxy,

(f) phenylacyloxy,

(g) phenoxycarbonyl,

(h) phenyl C₁₋₅ alkylacyloxy,

(i) phenyl C₁₋₅ alkoxy,

(j) amino,

(k) C₁₋₅ alkylamino,

(1) di(C₁₋₅ alkyl)amino,

(m) phenylamino,

(n) substituted phenylamino in which the substituents are X and Y;

(o) phenyl C₁₋₅ alkylamino,

(p) substituted phenyl C₁₋₅ alkylamino in which the substituents are Xand Y,

(q) C₃₋₈ cycloalkyl,

(r) phenyl,

(s) substituted phenyl in which the substituents are X and Y,

(t) phenylS(O)n,

(u) substituted phenyl S(O)n in which the substituents are X and Y,

(v) phenyl C₁₋₅ alkyl S(O)n,

(w) C₁₋₅ alkylS(O)n,

(x) phenylaminoacyloxy,

(y) C₁₋₅ alkylaminoacyloxy,

(z) C₁₋₅ alkylacylamino,

(aa) di(phenylC₁₋₅ alkyl)phosphonyl,

(bb) di(C₁₋₅ alkyl)phosphinyl,

(cc) phenylC₁₋₅ alkylacylamino;

(4) R₂ and R₃ together with the carbon atom to which they are attachedform a C₃₋₈ carbocyclic ring;

R₄ is selected from:

(1) hydrogen;

(2) C₁₋₅ alkyl;

(3) substituted C₁₋₅ alkyl in which the substituent is selected from

(a) phenyl,

(b) dimethylamino, and

(c) acetylamino, and

(4) 2,3 dihydroxypropyl;

R₁₃ is selected from:

(1) hydrogen;

(2) C₁₋₅ alkyl;

(3) substituted C₁₋₅ alkyl in which the substituent is selected from:

(a) phenyl,

(b) dimethylamino, and

(c) acetylamino, and

(d) hydroxy, provided that hydroxy is substituted only at C-2, C-3, C-4or C-5; and

(e) C₁₋₅ alkoxy;

(4) C₁₋₅ alkylcarbonyl;

(5) C₁₋₅ alkyloxycarbonyl;

(6) C₁₋₅ alkylaminocarbonyl;

X and Y independently are hydrogen, halogen, trifluoromethyl, C₁₋₃alkyl, nitro, cyano or a group selected from:

(1) R₆ O (CH₂)_(m) in which m is 0 to 3 and R₆ is hydrogen, C₁₋₃ alkylor hydroxy-C₂₋₃ alkyl;

(2) ##STR13## in which R₇ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl,phenyl, naphthyl,

amino-C₁₋₃ alkyl, C₁₋₃ alkylamino

C₁₋₃ alkyl, di(C₁₋₃ alkyl)amino-C₁₋₃ alkyl, hydroxy-C₂₋₃ alkylamino-C₁₋₃alkyl, or di(hydroxy-C₂₋₃ alkyl)amino-C₁₋₃ alkyl; provided that in##STR14## R₇ is not H; (3) ##STR15## in which R₈ is hydrogen, C₁₋₃alkyl, hydroxy-C₂₋₃ -alkyl, C₁₋₃ alkoxy C₁₋₃ alkyl, phenyl or naphthyl;

(4) R₉ R₁₀ N(CH₂)m,R₉ R₁₀ NC(CH₂)m ##STR16## in which R₉ and R₁₀independently are hydrogen, C₁₋₃ alkyl, hydroxy C₂₋₃ alkyl or R₉ and R₁₀together with the nitrogen atom to which they are attached form aheterocyclic group selected from piperidinyl, pyrrolidinyl, piperazinyl,morpholinyl or thiomorpholinyl;

(5) R₁₁ S(O)n(CH₂)_(m) in which R₁₁ is hydrogen, C₁₋₃ alkyl, amino, C₁₋alkylamino or di(C₁₋ alkyl)amino; is a single bond or a double bond;halogen is F or Cl;

or a pharmaceutically acceptable salt thereof.

Except where specifically defined to the contrary, the terms "alkyl","alkoxy" and "acyl" include both the straight-chain and branched-chainspecies of the term.

One embodiment of this invention is the class of compounds of theformulae (I) and (II) wherein:

A is O or S(O)n;

R₁ is selected from:

(1) C₁₋₁₀ alkyl;

(2) substituted C₁₋₁₀ alkyl in which one or more substituent(s) isselected from

(a) halogen,

(b) hydroxy,

(c) C₁₋₁₀ alkoxy,

(d) C₁₋₅ alkoxycarbonyl,

(e) C₁₋₅ acyloxy,

(f) C₃₋₈ cycloalkyl,

(g) phenyl,

(h) substituted phenyl in which the substituents are X and Y, and

(i) oxo;

(3) C₃₋₈ cycloalkyl;

(4) substituted C₃₋₈ cycloalkyl in which one substituent is selectedfrom

(a) C₁₋₁₀ alkyl,

(b) substituted C₁₋₁₀ alkyl in which the substituent is selected from

(i) halogen,

(ii) hydroxy,

(iii) C₁₋₁₀ alkoxy,

(iv) C₁₋₅ acyloxy,

(v) C₁₋₅ alkoxycarbonyl,

(vi) phenyl,

(vii) substituted phenyl in which the substituents are X and Y, and

(viii) oxo,

(c) halogen,

(d) hydroxy,

(e) C₁₋₁₀ alkoxy,

(f) C₁₋₅ alkoxycarbonyl,

(g) C₁₋₅ acyloxy,

(h) phenyl,

(i) substituted phenyl in which the substituents are X and Y;

(5) phenylamino;

(6) substituted phenylamino in which the substituents are X and Y;

(7) phenylC₁₋₁₀ alkylamino; and

(8) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are Xand Y;

R² and R³ are independently selected from

(1) hydrogen;

(2) C₁₋₁₀ alkyl;

(3) substituted C₁₋₁₀ alkyl in which one or more substituents isselected from:

(a) halogen,

(b) hydroxy, or

(c) amino;

(4) CH₂ R¹² in which R¹² is selected from:

(a) C₁₋₅ alkoxy,

(b) C₁₋₅ alkoxycarbonyl,

(c) C₁₋₅ alkylacyloxy,

(d) phenylacyloxy,

(e) phenoxycarbonyl,

(f) phenylC₁₋₅ alkylacyloxy,

(g) phenylC₁₋₅ alkoxy

(h) C₁₋₅ alkylamino,

(i) di(C₁₋₅ alkyl)amino,

(j) phenylamino,

(k) substituted phenylamino in which the substituents are X and Y,

(l) phenyl C₁₋₅ alkylamino,

(m) substituted phenyl C₁₋₅ alkyl amino in which the substituents are Xand Y,

(n) C₃₋₈ cycloalkyl,

(o) phenyl,

(p) substituted phenyl in which the substituents are X and Y,

(q) phenylS(O)_(n),

(r) substituted phenylS(O)_(n) in which the substituents are X and Y,

(s) phenyl C₁₋₅ alkylS(O)_(n),

(t) C₁₋₅ alkylS(O)n,

(u) phenylaminoacyloxy,

(v) C₁₋₅ alkylaminoacyloxy,

(w) C₁₋₅ alkylacylamino,

(x) di(phenylC₁₋₅ alkyl)phosphonyl,

(y) di(C₁₋₅ alkyl)phosphinyl,

(z) phenylC₁₋₅ alkylacylamino;

(5) R² and R³ together with the carbon atom to which they are attachedform a C₃₋₈ carbocyclic ring.

One subclass of this embodiment is the compounds of the formulae (I) and(II) wherein:

R₁ is selected from:

(1) C₁₋₁₀ alkyl;

(2) C₃₋₈ cycloalkyl;

(3) phenylamino; and

(4) substituted phenylamino in which the substituents are X and Y.

Illustrative of this subclass are those compounds of the formulae (I)and (II) wherein

R₂ and R₃ are independently selected from:

(1) hydrogen;

(2) C₁₋₅ alkyl;

(3) C₁₋₅ alkyl substituted with hydroxy;

(4) CH₂ R¹² in which R¹² is selected from:

(a) C₁₋₅ alkoxy,

(b) C₁₋₅ alkoxycarbonyl,

(c) C₁₋₅ alkylacyloxy,

(d) phenylacyloxy,

(e) phenoxycarbonyl,

(f) phenylC₁₋₅ alkylacyloxy,

(g) phenylC₁₋₅ alkoxy,

(h) phenyl S(O)_(n),

(i) substituted phenyl S(O)_(n) in which the substituents are X and Y,

(j) phenylC₁₋₅ alkyl S(O)_(n),

(k) C₁₋₅ alkyl S(O)_(n),

(l) phenylaminoacyloxy,

(m) C₁₋₅ alkylaminoacyloxy,

(n) phenyl,

(o) substituted phenyl in which the substituents are X and Y;

(p) C₁₋₅ alkylacylamino;

(q) phenylC₁₋₅ alkylacylamino;

(r) di(phenylC₁₋₅ alkyl)phosphon-yl;

(s) di(C₁₋₅ alkyl)phosphinyl

Further illustrating this subclass are those compounds of formulae (I)and (II) wherein:

A is O; a is a single bond; and

R₁ is 2-methyl-2-butyl or 2-butyl; and R₂ and R₃ are independentlyselected from: H, CH₃, phenylthiomethyl and hydroxymethyl.

Exemplifying this illustration are the following compounds of theformulae (I) and (II):

(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,-8a(R)-octahydronaphthyl1(S)]ethyl]4(R) hydroxy 3,4,5,6-tetrahydro-2H-pyran-2-one. (hereafterreferred to as compound 9)

(2) 6(R)-[2-[8(S)-methyl-5-oxa-6-(S)-(phenylthiomethyl, methyl)1,2,3,4,4a(R),7,8,8a(R) octahydronaphthyl-1(S)]-ethyl]-4(R) hydroxy3,4,5,6-tetrahydro-2H-pyran 2-one. (hereafter referred to as compound10)

(3) 6(R)-[2-[8(S)-(2,2 dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]4(R)hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. (hereafter referred to ascompound 11)

(4) 6(R)-[2[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octa-hydronaphthyl-1(S)]ethyl]4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(hydroxymethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(6)-6(R)-[2 [8(S)-(2,2-dimethylbutyryloxy) 2(S)- methyl-5 oxa-6(R)(hydroxymethyl, methyl) 1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(7)6(R)-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl,hydroxymethyl)-1,2,3,4,41(R),7,8,8a(R)-octahydro-naphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2Hpyran 2-one.

(8) 6(R) [2-[8(S) (2,2 dimethylbutyryloxy) 2(S) methyl 5-oxa 6(R)(phenylthiomethyl, hydroxymethyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl 1(S)]ethyl]-4(R)hydroxy 3,4,5,6 tetrahydro-2H-pyran-2-one.

A second illustration of this subclass are those compounds of formulae(I) and (II) wherein:

A is S(O)_(n) ; a is a single bond;

R₁ is 2-methyl-2-butyl or 2-butyl; and

R₂ and R₃ are independently selected from:

H, CH₃ and hydroxymethyl.

Exemplifying this second illustration are the following compounds offormulae (I) and (II):

(11) 6(R)-[2[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-thia-6,6-dimethyl1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one.

(2) 6(R) [2-[8(S) (2,2-dimethylbutyryloxy)-2(S)-methyl-5 thia 6(S)(hydroxymethyl, methyl) 1,2,3,4,4a,7,8,8a(R)octahydronaphthyl-1(S)]ethyl]4(R) hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one.

(3) 6(R) [2-[8(S)-(2,2-dimethylbutyryloxy)-2-(S)-methyl-5-thia6(R)-(hydroxymethyl,methyl)-1,2,3,4,4a,7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(4) 6(R) [2-[8(S)-(2,2 dimethylbutyryloxy) 2(S) methyl thia6(S)-(hydroxymethyl)1,2,3,4,4a,6,7,8,8a(R)-nonahydronaphthyl-1(S)]ethyl]4(R)hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one.

(5) 6(R) [2 [8(S) (2,2 dimethylbutyryloxy) 2(S) methyl thia 6(R)(hydroxymethyl) 1,2,3,4,4a,6,7,8,8a(R) nonahydronaphthyl 1(S)]ethyl]4(R)hydroxy 3,4,5,6- tetrahydro-2H-pyran 2 one.

(6) 6(R) [2 [8(S) (2,2 dimethylbutyryloxy)-2(S)-methyl-thia-5,5 dioxide6,6 dimethyl 1,2,3,4,4a(R),7,8,- a(R)-octahydronaphthyl-1(S)]ethyl]4(R)hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

In a second embodiment is the compounds of formula (I) and (II) wherein

A is N-R¹³ ;

R₁ is selected from:

(1) C₁₋₁₀ alkyl;

(2) substituted C₁₋₁₀ alkyl in which one or more substituent(s) isselected from

(a) halogen,

(b) hydroxy,

(c) C₁₋₁₀ alkoxy,

(d) C₁₋₅ alkoxycarbonyl,

(e) C₁₋₅ acyloxy,

(f) C₃₋₈ cycloalkyl,

(g) phenyl,

(h) substituted phenyl in which the substituents are X and Y, and

(i) oxo;

(3) C₃₋₈ cycloalkyl;

(4) substituted C₃₋₈ cycloalkyl in which one substituent is selectedfrom

(a) C₁₋₁₀ alkyl,

(b) substituted C₁₋₁₀ alkyl in which the substituent is selected from

(i) halogen,

(ii) hydroxy,

(iii) C₁₋₁₀ alkoxy

(iv) C₁₋₅ acyloxy,

(v) C₁₋₅ alkoxycarbonyl,

(vi) phenyl,

(vii) substituted phenyl in which the substituents are X and Y, and

(viii) oxo,

(c) halogen,

(d) hydroxy,

(e) C₁₋₁₀ alkoxy,

(f) C₁₋₅ alkoxycarbonyl,

(g) C₁₋₅ acyloxy,

(h) phenyl,

(i) substituted phenyl in which the substituents are X and Y;

(5) phenylamino;

(6) substituted phenylamino in which the substituents are X and Y;

(7) phenylC₁₋₁₀ alkylamino; and

(8) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are Xand Y;

R² and R³ are independently selected from

(1) hydrogen;

(2) C₁₋₁₀ alkyl;

(3) substituted C₁₋₁₀ alkyl in which one or more substituents isselected from:

(a) halogen,

(b) hydroxy,

(c) amino;

(4) CH₂ R¹² in which R¹² is selected from:

(a) C₁₋₅ alkoxy,

(b) C₁₋₅ alkoxycarbonyl,

(c) Cl5 alkylacyloxy,

(d) phenylacyloxy,

(e) phenoxycarbonyl,

(f) phenylC₁₋₅ alkoxy,

(h) C₁₋₅ alkylamino,

(i) di(C₁₋₅ alkyl)amino,

(j) phenylamino,

(k) substituted phenylamino in which the substituents are X and Y,

(l) phenyl C₁₋₅ alkylamino,

(m) substituted phenyl C₁₋₅ alkyl amino in which the substituents are Xand Y,

(n) C₃₋₈ cycloalkyl,

(o) phenyl,

(p) substituted phenyl in which the substituents are X and Y,

(q) phenylS(O)_(n),

(r) substituted phenylS(O)_(n) in which the substituents are X and Y,

(s) phenyl C₁₋₅ alkylS(O)_(n),

(t) C₁₋₅ alkylS(O)_(n),

(u) phenylaminoacyloxy,

(v) C₁₋₅ alkylaminoacyloxy,

(w) C₁₋₅ alkylacylamino,

(x) di(phenylCI 5alkyl)phosphonyl,

(y) di(C₁₋₅ alkyl)phospinyl;

(5) R² and R³ together with the carbon atom to which they are attachedform a C₃₋₈ carbocyclic ring.

One subclass of this embodiment is the compounds of the formulae (I) and(II) wherein:

R₁ is selected from:

(1) C₁₋₁₀ alkyl;

(2) C₃₋₈ cycloalkyl;

(3) phenylamino; and

(4) substituted phenylamino in which the substituents are X and Y.

R₁₃ is selected from:

(1) hydrogen;

(2) C₁₋₅ alkyl;

(3) phenylC₁₋₅ alkyl;

(4) C₁₋₅ alkylcarbonyl.

Illustrative of this subclass are those compounds of the formulae (I)and (II) wherein R₂ and R₃ are independently selected from:

(1) hydrogen;

(2) C₁₋₅ alkyl;

(3) C₁₋₅ alkyl substituted with hydroxy;

(4) CH₂ R¹² in which R¹² is selected from:

(a) C₁₋₅ alkoxy,

(b) C₁₋₅ alkoxycarbonyl,

(c) C₁₋₅ alkylacyloxy,

(d) phenylacyloxy,

(e) phenoxycarbonyl,

(f) phenylC₁₋₅ alkylacyloxy,

(g) phenylC₁₋₅ alkoxy,

(h) phenyl S(O)_(n),

(i) substituted phenyl S(O)_(n) in which the substituents are X and Y,

(j) phenylalkyl S(O)_(n),

(k) C₁₋₅ alkyl S(O)_(n),

(l) phenylaminoacyloxy,

(m) C₁₋₅ alkylaminoacyloxy,

(n) phenyl,

(o) substituted phenyl in which the substituents are X and Y.

The compounds of formula (I) wherein A is O and a is a single bond areprepared following Scheme 1: ##STR17##

Compound (1-1) may be prepared from lovastatin or mevastatin byreplacement, if necessary, of the 2-methylbutyryloxy moiety by R₁ CO₂.The hydrolysis of the 8-acyloxy moiety and reesterification may beaccomplished following the procedure in U.S. Pat. No. 4,444,784. Theconversion to compounds (1-1) wherein Q is CH₂ OH and its silylprotected form can be carried out following the procedures in U.S.patent applications Ser. No. 161530, Ser. No. 161579, Ser. No. 161529all filed on Feb. 29, 1988.

Compound (1-1) is converted to compound (1-2) by the reduction of the3,4-double bond following the detailed procedure in U.S. patentapplication Ser. No. 092,804 filed Sept. 3, 1987.

The monoene (1 2) is treated with ozone in methanol at about -78° C.followed by reduction of the ozonide with Zn/acetic acid and reductionof the intermediate ketoaldehyde with NaBH₄ to yield compound (1-3)which after contact with tosyl chloride gives the tosylate (1-4).Treatment of the tosylate (1 4) with sodium iodide in acetone gives aniodide (1-5). Compound (1-7) is obtained from the iodide (1 5) byselenation with o-O₂ NPhSeCN followed by oxidative elimination withTHF/H₂ O₂. Treatment of compound (1-7) with iodine/CH₂ Cl₂ in thepresence of NaHCO₃ yields compound (1-8) as a mixture of epimers. Theepimeric iodides (1-8) can be reduced with a trialkyl tin hydride toafford compounds (1-9). Alternatively (Scheme 2), the epimeric iodides(1 8) can be converted to compounds of formula (2 10) by reaction withan alkyl or heteroatom moiety either by a substitution or radicalcoupling reaction. One example of such methodology is the cross couplingreaction between an alkyl halide and an organo metallic reagent (e.g.alkyl iodides with lithium dialkylcopper-Posner, Org. React. 22, 253-400(1975)). ##STR18##

In the preparation of compounds (I), where R₂ and R₃ are both alkylother than methyl or both substituted alkyl, compounds of formula (1-1)are utilized wherein Q is t-Bu(Me)₂ SiOCH₂. The silyloxy protectinggroup of compound (2 10) is removed employing standard techniques andthe resulting hydroxymethyl moiety is halogenated, e.g.triphenyl-phosphine, iodine, imidazole, followed by substitution orradical coupling with an alkyl or heteroatom moiety which results in theelaboration of CH₂ I to R³ (Scheme 2a). ##STR19##

Compounds of formulae (I) and (II) wherein a is a double bond may beprepared following the methodology of Scheme 3. This scheme employssimilar sequences to that of Scheme 1 but uses one equivalent of NaBH₄to reduce the ketoaldehyde, formed from the Zn/HOAc treatment of theozonide, to the ketone (3--3) which is followed by a Pd catalyzeddehydrogenation to insert the 3,4-double bond. The ketone (3-4) is thenreduced with a second equivalent of NaBH₄. The primary alcohol (3-5) isiodinated (3-6), converted to the selenium derivative (3-7) and oxidizedto the olefin (3-8). Treatment of compound (3-8) with iodine/CH₂ Cl₂ inthe presence of NaHCO₃ yields compounds (3 9) as a mixture of epimers.The epimeric iodides (3-9) can be reduced to compounds of formula (3-10)by reaction with a trialkyl tin hydride. ##STR20##

Alternatively one can start with a hexahydronaphthyl moiety as in Scheme2 and protect the 3,4 double bond, using the method described by Kuo inU.S. Pat. No. 4,490,546, while the chemical transformations of Scheme 1are conducted at the 4a, 5 and 6 sites. The protecting group isultimately removed following the procedure of Kuo.

The compounds of formulae (I) and (II) wherein A is S(O)_(n) areprepared following Schemes 4 and 4a. The lactone is reduced withdiisobutyl aluminum hydride (DIBAL) followed by reaction with methanoland para-toluene sulfonic acid (PTSA) to form the acetal (4-4). Acetal(4-4) is then carried throuqh a series of reactions, analogous to thosediscussed in Scheme 1, to form the olefin (4-8). The 4a alcohol group ofCompound (4-8) is converted to the ketone (4-9) via a Swern oxidation.If desired a double bond can be inserted into the 3,4-position ofCompound (4-9) by a Pd catalyzed dehydrogenation to form Compound(4-10). The 4a-keto moiety of Compound (4-10) is converted to athioketone (4-11) by employing 2,4 bis(4 methoxyphenyl) 1,3,2,4dithiadi- phosphetane-2,4 disulfide and following the procedure ofPederson et al., Bull. Soc. Chem. Belg., 87 223, (1978). The thioketone(4-11) is reduced to the mercaptan (4-12) followed by cyclization to thesulfide (4-13) employing the method described by Stacey et al., OrganicReactions, Vol. 13, p. 150, John Wiley & Sons (1963). The acetal moietyis converted back to the lactone, the hydroxyl protecting group removed,and if desired the sulfide group oxidized with m chloroperbenzoic acid(m-CPBA) to form Compound (4-14) The hydroxymethyl moiety of Compound(4-14) can be elaborated to R₂ (Compound (4-15)) by conversion to thehalomethyl group followed by substitution or coupling with an alkyl orheteroatom moiety as discussed above in Scheme 2. The identity andemployment of Q is analogous to that previously discussed in Schemes 2and 3.

In Scheme 4a, azaisobutyronitrile (AIBN) is employed in the cyclizationstep to form Compound (4-16) which is then transformed as describedabove to ultimately form Compound (4-19). ##STR21##

The compounds of formula (I) and (II) wherein A is N-R¹³ are preparedfollowing Scheme 5. The conversions in Scheme 5 proceeding to ketone(5-7) are analogous to those described earlier in Schemes 1 and 4. Theinsertion of nitrogen is accomplished through a reductive aminationutilizing benzylamine (BnNH₂) and resulting in Compound (5-8). The amine(5-8) is converted to a carbamate (5-9) and then cyclized to the 5-azaanalog (5-10) following the procedure of Newcomb et al., TetrahedronLetters, 26, 5651, (1985) and J. Am. Chem. Soc., 109, 3163 (1987). Thehydroxyl protecting is removed employing tetra-butylammonium fluorideand the N-benzyl group replaced by N--H by reaction with H₂ /Pd/C. Theidentity and employment of Q in Scheme 5 is analogous to that aspreviously discussed in Schemes 2 and 3. If desired the 3,4- double bondcan be inserted in the aza compounds by reaction of Compound (5-7) withPdCl₂ /Pd(OAc)₂ following an analogous methodology to that expressed inScheme 4. The enone product is then transformed further to Compound(5-8) etc. following the reactions of Scheme 5. ##STR22##

Where the reaction conditions of the above described chemicaltransformations would be deleterious to the substituents contained inR₁, the acetoxy group can be employed as a protecting group which afterthe insertion of the 5-heteroatom moiety and the elaboration of the 6,6positions can be removed by hydrolysis to give the 8 hydroxy derivativewhich can then be acylated according to the general procedures describedin U.S. Pat. No. 4,661,483 and co pending U.S. applications Ser. No.859,513, 859,524, 859,525, 859,520, 859,534 and 859,535 all filed on May5, 1986. The alkanoyl chloride for preparing the 8-acyloxy moiety can beformed by standard chemical transformations such as substitution with analkyl moiety or other appropriate electrophile at an acidic C-H site onan available starting material; more specifically the 8-acyloxy moietycan be prepared following the descriptions in the aforementionedcopending patent applications filed on May 5, 1986.

It may be necessary to protect substituents on the R₂, R₃ moietiesduring such chemical transformations as compounds (1-8)→compounds(2-10). Suitable protective groups can be found in Protective Groups inOrganic Synthesis, Greene, John Wiley & Sons (1981).

Where the product formed by the above described synthetic pathways isnot the desired form of that compound, then that product may besubjected to one or more further reactions such as hydrolysis,salification, esterification, acylation, ammonolysis, desilylation orlactonization by conventional methods, as described in more detailhereafter.

Preferred metal salts are salts with alkali metals, such as sodium orpotassium, salts with alkaline earth metals, such as calcium, or saltswith other metals such as magnesium, aluminum, iron, zinc, copper,nickel or cobalt, of which the alkali metal, alkaline earth metal,magnesium and aluminum salts are preferred, the sodium, calcium andaluminum salts being most preferred.

Preferred amino acids to form amino acid salts are basic amino acids,such as arginine, lysine, α,β-diaminobutyric acid or ornithine.

Preferred amines to form amine salts include t-octylamine,dibenzylamine, ethylenediamine, morpholine, andtris(hydroxymethyl)aminomethane. Also preferred is ammonia to form theammonium salt.

Esters are preferably the alkyl esters, such as the methyl, ethyl,propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methylester is preferred. However, other esters such as phenyl C₁₋₅ alkyl,dimethylamino C₁₋₅ alkyl, or acetyl amino-C₁₋₅ alkyl may be employed ifdesired.

Metal salts of the carboxylic acids of formula (II) may be obtained bycontacting a hydroxide, carbonate or similar reactive compound of thechosen metal in an aqueous solvent with the carboxylic acid of formula(II). The aqueous solvent employed is preferably water, or it may be amixture of water with an organic solvent, preferably an alcohol (such asmethanol or ethanol), a ketone (such as acetone), an aliphatichydrocarbon (such as hexane) or an ester (such as ethyl acetate). It ispreferred to use a mixture of a hydrophilic organic solvent with water.Such reactions ar normally conducted at ambient temperature but theymay, if desired, be conducted with heating or cooling.

Amine salts of the carboxylic acids of formula (II) may be obtained bycontacting an amine in an aqueous solvent with the carboxylic acid offormula (II). Suitable aqueous solvents include water and mixtures ofwater with alcohols (such as methanol or ethanol), ethers (such asdiethyl ether and tetrahydrofuran), nitriles (such as acetonitrile) orketones (such as acetone); it is preferred to use aqueous acetone as thesolvent for this reaction. The reaction is preferably carried out at atemperature of ambient or below, more preferably a temperature of from5° to 10° C. The reaction immediately goes to completion. Alternatively,a metal salt of the carboxylic acid of formula (II) (which may have beenobtained as described above) can be dissolved in an aqueous solvent,after which a mineral acid salt (for example the hydrochloride) of thedesired amine is added, employing the same reaction conditions as whenthe amine itself is reacted with the carboxylic acid of formula (II) andthe desired product is then obtained by metathesis.

Amino acid salts of the carboxylic acids of formula (II) may be obtainedby contacting an amino acid in aqueous solution with the carboxylic acidof formula (II). Suitable aqueous solvents include water and mixtures ofwater with alcohols (such as methanol or ethanol) or ethers (such astetrahydrofuran).

Esters, preferably alkyl esters, of the carboxylic acids of formula (II)may be obtained by contacting the carboxylic acid of formula (II) withan appropriate alcohol, preferably in the presence of an acid catalyst,for example a mineral acid (such as hydrochloric acid or sulphuricacid), a Lewis acid (for example boron trifluoride) or an acidic ionexchange resin. The solvent employed for this reaction is not critical,provided that it does not adversely affect the reaction; suitablesolvents include the alcohol itself, benzene, chloroform, ethers and thelike. Alternatively, the desired product may be obtained by contactingthe carboxylic acid of formula (II) with a diazoalkane, in which thealkane moiety may be substituted or unsubstituted. This reaction isusually effected by contacting the acid with an ethereal solution of thediazoalkane. As a further alternative, the ester may be obtained bycontacting a metal salt of the carboxylic acid of formula (II) with ahalide, preferably an alkyl halide, in a suitable solvent; preferredsolvents include dimethylformamide, tetrahydrofuran, dimethylsulfoxideand acetone. Finally, esters may also be obtained from the lactone offormula (I) by reaction with an appropriate alkoxide in an absolutealkanol. All of the reactions for producing esters are preferablyeffected at about ambient temperature, but, if required by the nature ofthe reaction system, the reactions may be conducted with heating orcooling.

Lactones of the carboxylic acids of formula (I) may be obtained bylactonizing the carboxylic acids of formula (II) under ordinaryconditions known to one skilled in the art.

The intrinsic HMG--CoA reductase inhibition activity of the claimedcompounds is measured in the in vitro protocol published in J. Med.Chem., 28, p. 347-358 (1985).

For estimation of relative inhibitory potencies, compactin (i.e.,mevastatin) was assigned a value of 100 and the IC₅₀ value of the testcompound was compared with that of compactin determined simultaneouslyin the published in vitro protocol.

Representative of the intrinsic HMG-CoA reductase inhibitory activitiesof the claimed compounds are the following potencies.

    ______________________________________                                        Compound                              Relative                                No.      R.sub.1      R.sub.2  R.sub.3                                                                              Potency                                 ______________________________________                                        9        2-methyl-2-butyl                                                                           CH.sub.3 CH.sub.3                                                                              96                                     10 (α-epimer)                                                                    2-methyl-2-butyl                                                                           CH.sub.3 PhSCH.sub.2                                                                          258                                     11 (β-epimer)                                                                     2-methyl-2-butyl                                                                           PhSCH.sub.2                                                                            CH.sub.3                                                                             280                                     ______________________________________                                    

The compounds of this invention are useful as antihypercholesterolemicagents for the treatment of arteriosclerosis, hyperlipidemia, familialhypercholesterolemia and like diseases in humans. They may beadministered orally or parenterally in the form of a capsule, a tablet,an injectable preparation or the like. It is usually desirable to usethe oral route. Doses may be varied, depending on the age, severity,body weight and other conditions of human patients but daily dosage foradults is within a range of from about 10 mg to 2000 mg (preferably 10to 100 mg) which may be given in two to four divided doses. Higher dosesmay be favorably employed as required.

The compounds of this invention may also be coadministered withpharmaceutically acceptable nontoxic cationic polymers capable ofbinding bile acids in a non-reabsorbable form in the gastrointestinaltract. Examples of such polymers include cholestyramine, colestipol andpoly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide]. Therelative amounts of the compounds of this invention and these polymersis between 1:100 and 1:15,000.

Included within the scope of this invention is the method of treatingarteriosclerosis, familial hypercholesterolemia or hyperlipidemia whichcomprises administering to a subject in need of such treatment anontoxic, therapeutically effective amount of the compounds of formulae(I) or (II) or pharmaceutical compositions thereof.

The following examples illustrate the preparation of the compounds ofthe formulae (I) and (II) and their incorporation into pharmaceuticalcompositions and as such are not to be considered as limiting theinvention set forth in the claims appended hereto.

EXAMPLE 1 Preparation of6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-oneStep 1: Preparation of6(R)-[2-(8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6(R)-methyl-1,2,3,4,6,7,8,8a(S)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(2)

Nitrogen was bubbled through a solution of 50% toluene in absoluteethanol (300 mL) for 5 minutes. Wilkinson's catalyst (5.0 g, 33%/wt.)was added to the solvent and the mixture reduced at room temperatureunder 50 psi H₂ for 1 hour. Simvastatin (15 g, 36 mmol) was added andthe resulting pale yellow solution reduced at room temperature under H₂(60 psi) for 40 hours. The mixture was concentrated and the residueheated in toluene (700 mL) at 60° C. in the presence of thiourea (5.0 g,64 mmol) for 1.5 hours. The mixture was cooled to 0° C. (ice bath),filtered, and concentrated. The residue was diluted with 50%EtOAc/hexane and passed through a pad of silica (˜250 cc) to give 2 as abeige solid; mp=128°-129° C. (ethyl/hexane); TLC Rf=0.65 (EtOAc); ¹ HNMR (CDCl₃) δ5.36 (bs, 1H), 5.30 (m,1H), 4.58 (m,1H), 4.33 (m, 1H), 2.68(dd,J=17 and 5Hz,1H), 2.68 (m,1H), 2.59 (dd, J=17 and 4Hz,1H), 2.30 1.20(m), 1.13 (s,3H), 1.12 (s,3H), 1.05 (d, J=7Hz,3H), 0.87 (d, J=7Hz,3H),0.82 (t, J=7Hz,3H). Step 2: Preparation of6(R)-[2-[6(R)-(1(S)-2,2-dimethylbutyryloxy-3(R)-methylbutan-4-ol)-2(S)-methyl-5(R)-hydroxy-cyclohexyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(3).

Ozone was passed through a red solution of monoene 2 (420 mg, 1.0 mmol)and 1-(p-phenylazophenylazo)-2-naphthol (sudan III) (5 mg) in CH₃ OH (10mL) at -78° C. until the red color dissipated (10 minutes). Argon wasthen bubbled through the solution to remove excess ozone. Addition ofzinc (200 mg, 3.0 mmol) and acetic acid (1.0 mL) was followed by removalof the cooling bath and vigorous stirring for 15 minutes. The reactionmixture was diluted with ethyl acetate and filtered through celite. Thefiltrate was washed with H₂ O and brine, dried (MgSO₄), andconcentrated. The crude keto-aldehyde was immediately dissolved inTHF/H₂ O (10:1, 8.0 mL), cooled to 0° C., and treated with NaBH₄ (100mg, 3.0 mmol) in 2 portions. After 20 minutes the reaction mixture wasdiluted with ethyl acetate, washed with H₂ O, and brine, dried (MgSO₄),and concentrated. Flash chromatography (silica, EtOAc) gave the desiredproduct as an oil.

¹ H NMR (CDCl₃): δ5.55 (m, 1H), 4.72 (m, 1H), 4.38 (m, 1H), 3.61 (dd,1H, J=10 and 3Hz), 3.44 (dd, 1H, J=10 and 3Hz), 3.39 (m, 1H), 2.73 (dd,1H, J=15 and 3Hz), 2.63 (m, 1H), 2.01-1.20 (m), 1.15 (s, 6H), 0.96 (d,3H, J=4Hz), 0.85 (t, 3H, J=6Hz) 0.83 (d, 3H, J=7Hz).

Elemental Anal. C₂₅ H₄ O₇.1.OH₂ O Calc'd: C, 63.26; H, 9.77. Found: C,63.13; H, 9.51.

Step 3: Preparation of6(R)-[2-[6(R)-(1(S)-2,2-dimethylbutyryloxy-3(R)-methyl-4-p-toluenesulfonyl-butane)-2(S)-methyl-5(R)-hydroxycyclohexyl1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (4)

To a stirred solution of the triol 3 (100 mg, 0.22 mmol), pyridine (71ml, 1.0 mmol), and dry CH₂ Cl₂ (1.1 mL) at 0° C. was addedp-toluenesulfonyl chloride (50 mg, 0.26 mmol). After 5 minutes thecooling bath was removed and the reaction stirred overnight. Thereaction mixture was diluted with ethyl acetate, washed with H₂ O andbrine, dried (MgSO₄), and concentrated. Flash chromatography (silica, 8%acetone/CH₂ Cl₂) furnished the desired product as a colorless foam.

¹ H NMR (CDCl₃): δ7.75 (d, 2H, J=8Hz), 7.31 (d, 2H, J=8Hz), 5.45 (m,1H), 4.66 (m, 1H), 4.33 (m, 1H), 4.02 (dd, 1H, J=10 and 5Hz), 3.79 (dd,1H, J=10 and 4Hz), 3.32 (m, 1H), 2.63 (m, 2H), 2.40 (S, 3H), 2.00-1.20(m), 1.10 (S, 6H), 0.90 (d, 3H, J=7Hz), 0.80 (d, 3H, J=7Hz), 0.78 (t,3H, J=7Hz).

Step 4: Preparation of 6(R)-[2-[6(R)-(1(S)-2,2-dimethylbutyryloxy3(R)-methyl-4-iodo-butane)-2(S)-methyl-5(R)-hydroxy-cyclohexyl-1(S)]ethyl]-4(R)-hydroxy3,4,5,6-tetrahydro-2-H-pyran-2-one (5)

A stirred mixture of the tosylate 4 (0.80 g, 1.3 mmol), NaI (1.2 g, 7.8mmol), and acetone (8.0 mL) was heated to reflux for 2.0 h. The cooledreaction mixture was diluted with ether, washed sequentially with H₂ O,10% Na₂ SO₃, and brine, dried (MgSO₄), and concentrated. Flashchromatography (silica, ether) gave the desired product 5 as a colorlessoil.

¹ H NMR (CDCl₃): δ5.44 (m, 1H), 4.68 (m, 1H), 4.37 (m, 1H), 3.40 (m,1H), 3.32 (dd, 1H, J=15 and 5Hz), 3.25 (dd, 1H, J=15 and 3Hz), 2.70 (dd,1H, J=15 and 4Hz), 2.61 (m, 1H), 2.00-1.28 (m), 1.13 (S, 6H), 0.98 (d,3H, J=7Hz), 0.83 (t, 3H, J=7Hz), 0.82 (d, 3H, J=7Hz).

Step 5: Preparation of6(R)-[2-[6(R)-(1(S)-2,2-dimethylbutyryloxy-3(R)-methyl-4-o-nitrophenylseleno-butane)-2(S)-methyl-5(R)-hydroxy-cyclohexyl-1(S)]ethyl]-e(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(6)

A stirred solution of the iodide 5 (208 mg, 0.37 mmol), 2-nitrophenylselenocyanate (167 mg, 0.75 mmol), and dry DMF (2.0 ml) was degassed,cooled to 0° C. and then treated with NaBH₄ (14 mg, 0.37 mmol). After 10minutes the cooling bath was removed and the mixture stirred for 2.0hours. The reaction mixture was diluted with ethyl acetate, washed withH₂ O and brine, dried (MgSO₄), and concentrated. Flash chromatography(silica, 70% EtOAc/hexane) afforded the desired product 6 as a yellowoil.

¹ H NMR (CDCl₃): δ8.23 (m, 1H), 7.54 (m, 2H), 7.28 (m, 1H), 5.60 (m,1H), 4.67 (m, 1H), 4.38 (m, 1H), 3.35 (m, 1H), 3.05 (dd, 1H, J=11 and4Hz), 2.80 (dd, 1H, J=11 and 4Hz), 2.68 (m, 2H), 2.00-1.30 (m), 1.55 (S,3H), 1.54 (d, 3H), 1.16 (d, 3H), 1.14 (S, 3H), 0.81 (t, J=6Hz).

Step 6: Preparation of6(R)-[2-[6(R)-(1(S)-2,2-dimethylbutyryloxy-3-methyl-3-butene)-2(S)-methyl-5-(R)-hydroxy-cyclohexyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2-H-pyran-2-one(7)

To a stirred solution of the selenide 6 (250 mg, 0.33 mmol) in THF (3ml) at 0° C. was added 30% H₂ O₂ (75 μl, 0.66 mmol) dropwise. After 5minutes the cooling bath was removed and the reaction mixture stirredovernight. The orange solution was diluted with ethyl acetate, washedwith sat. NaHCO₃ and brine, dried (MgSO₄), and concentrated. Flashchromatography (silica, ether) furnished the desired product 7 as anoil.

¹ H NMR (CDCl₃): δ5.48 (m, 1H), 4.78(d,2H,J=5Hz) 4.70 (m, 1H), 4.40 (m,1H), 3.43 (m, 1H), 2.74 (dd, 1H, J=16 and 3Hz), 2.64 (m, 1H), 2.55-2.27(m, 2H), 2.05-1.24 (m), 1.15 (s, 6H), 0.85 (d, 3H, J=7Hz), 0.84 (t, 3H,J=7Hz).

Elemental Anal. C₂₅ H₄₂ O₆.0.5 H₂ O: Calc'd: C, 67.08; H, 9.68. Found:C, 66.91; H, 9.61.

Step 7: (a) Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)methyl-5-oxa-6(S)-(iodomethyl, methyl)-1,2,3,4,4a(R),7,8,8a-(R)-octahydronaphthyl-1(S)]ethyl]4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(8a)(b)6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(iodomethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(8b)

A stirred mixture of the olefin 7 (149 mg, 0.34 mmol), NaHCO₃ (115 mg,1.3 mmol), and CH₂ Cl₂ (3.4 mL) at 0° C. was treated with iodine (173mg, 0.68 mmol) in one portion. After 15 minutes the dark red mixture wasdiluted with ethyl acetate, washed sequentially with H₂ O, 10% Na₂ SO₃,and brine, dried (MgSO₄), and concentrated. Flash chromatography(silica, ether) afforded the crude product 8 (1:1 mixture of epimers) asa red oil.

¹ H NMR of mixture (CDCl₃): δ5.20 (m, 1H), 4.58 (m, 1H), 4.35 (m, 1H),3.79 (d, 0.5H, J=8Hz), 3.61 (m, 0.5H), 3.48 (m, 0.5H), 3.34 (d, 0.5H,J=8Hz), 3.17 (m, 1H), 2.71 (dd, 1H, J=15 and 5Hz), 2.30-1.10 (m), 0.84(m, 6H).

Step 8: 6(R)[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(9)

A stirred mixture of iodides 8 (153 mg, 0.27 mmol), tributyltin hydride(237 μl, 0.81 mmol), and azaisobutyronitrile (AIBN) (2 mg) in degassedtoluene (1.4 ml) was heated at 80° C. for 4.0 hours. The cooled reactionmixture was concentrated to dryness. The residue was dissolved in CH₃ CN(10 ml) and washed with hexanes (10×).

The hexane washes, containing tin byproducts, were decanted away fromthe acetonitrile. The acetonitrile was evaporated and the residuesubjected to flash chromatography (silica, 20% EtOAc/CH₂ Cl₂) to furnishthe crude product. The crude material was purified by preparative plate(0.5 mm, silica, 20% EtOAc/CH₂ Cl₂) chromatography to yield the desiredproduct 9 as a colorless oil.

¹ H NMR (CDCl₃): δ5.20 (m, 1H), 4.59 (m, 1H), 4.37 (m, 1H), 3.63 (m,1H), 2.73 (dd, 1H, J=16 and 4Hz), 2.61 (m, 1H), 2.00-1.15 (m), 1.32 (S,3H), 1.27 (S, 3H), 1.25 (S, 3H), 1.24 (S, 3H), 0.87 (d, 3H, J=6Hz), 0.84(t, 3H, J=7Hz).

Elemental Anal. C₂₅ H₄₂ O₆.1.0H₂ O: Calc'd: C, 67.23; H, 9.93. Found: C,66.87; H, 9.61.

EXAMPLE 2 Preparation of6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]4(R)-hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one. (10) (R)6[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(11)

Steps 1-7 were repeated following the procedure of Example 1.

Step 8: Preparation of6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl,methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1-(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (10)6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl,methyl)-1,2,3,4,4a(R),7,-8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4-(R)-hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one (11)

A degassed solution of iodides 8 (120 mg, 0.21 mmol), thiophenol (110μl, 1.0 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (150 μl, 1.0 mmol),and dry DMF was heated at 80° C. for 4.0 hours. The cooled reactionmixture was diluted with ether, washed with H₂ O (2×) and brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 80%EtOAc/hexane) gave a 1:1 mixture of epimers as a colorless oil.Separation of the epimers was accomplished by preparative platechromatography (0.5 mm silica, 65% EtOAc/benzene) to furnish the fastermoving α-epimer 10 and the slower moving β-epimer 11 as colorless oils.

αepimer: ¹ H NMR (CDCl₃): δ7.40-7.10 (m, 5H), 5.23 (bs, 1H), 4.56 (m,1H), 4.34 (m, 1H), 3.62 (m, 1H), 3.06 (d, 1H, J=13Hz), 2.95 (d, 1H,J=13Hz), 2.70 (dd, 1H, J=15 and 5Hz), 2.58 (dd, 1H, J=15 and 2Hz), 2.14(m, 1H), 2.00-1.14 (m), 1.40 (S, 3H), 1.17 (S, 3H), 1.16 (S, 3H), 0.84(d, 3H, J=7Hz), 0.83 (t, 3H, J=7Hz).

β-epimer: ¹ H NMR (CDCl₃): δ7.40-7.10 (m, 5H), 5.20 (m, 1H), 4.56 (m,1H), 4.33 (m, 1H), 3.64 (d, 1H, J=12Hz), 3.48 (m, 1H), 3.04 (d, 1H,J=12Hz), 2.70 (dd, 1H, J=15 and 5Hz), 2.58 (m, 1H), 2.22-1.10 (m), 1.29(S, 3H), 1.13 (S, 3H), 1.12 (S, 3H), 0.83 (d, 3H, J=7Hz), 0.82 (t, 3H,J=7Hz).

EXAMPLE 3 Preparation of 6(R)[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)ethyl]-4(R)hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (12)

Utilizing the general procedure of Example 1 but substituting6(R)-[2-8(S)-(2-methylbutyryloxy)-2(S)-methyl-6(R)-methyl1,2,6,7,8,8a(R)-hexahydro-naphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one,for the starting polyhydronaphthyl moiety, the titled compound isprepared.

EXAMPLES 4-33

Utilizing the general procedures in Examples 1-2 and, where a is adouble bond, the modifications of Scheme 3, the following compounds offormula I wherein R₁ =2-methyl-2-butyl and A=O are prepared from theappropriately substituted starting materials.

    ______________________________________                                        Compound                                                                      No.      R.sub.2        R.sub.3        a                                      ______________________________________                                        13       CH.sub.2 OH    CH.sub.3       sb                                     14       CH.sub.3       CH.sub.2 OH    sb                                     15       CH.sub.2 OH    CH.sub.2 SPh   sb                                     16       CH.sub.2 SPh   CH.sub.2 OH    sb                                     17       CH.sub.3       CH.sub.3       db                                     18       CH.sub.2 OH    CH.sub.3       db                                     19       CH.sub.3       CH.sub.2 OH    db                                     20       CH.sub.2 OH    CH.sub.2 SPh   db                                     21       CH.sub.2 SPh   CH.sub.2 OH    db                                     22       CH.sub.3       CH.sub.2 SPh   db                                     23       CH.sub.2 SPh   CH.sub.3       db                                     24       H              CH.sub.3       sb                                     25       CH.sub.3       H              sb                                     26       CH.sub.2 OH    H              sb                                     27       H              CH.sub.2 OH    sb                                     28       CH.sub.2 OCH.sub.3                                                                           CH.sub.3       sb                                     29       CH.sub.3       CH.sub.2 OCH.sub.3                                                                           sb                                     30       CH.sub.2 OC(O)NHPh                                                                           CH.sub.3       sb                                     31       CH.sub.3       CH.sub.2 OC(O)NHPh                                                                           sb                                     32       CH.sub.2 SCH.sub.2 Ph                                                                        H              sb                                     33       H              CH.sub.2 SCH.sub.2 Ph                                                                        sb                                     34       CH.sub.2 NHC(O)CH.sub.3                                                                      CH.sub.3       sb                                     35       CH.sub.3       CH.sub.2 NHC(O)CH.sub.3                                                                      sb                                     36       H              CH.sub.2 NHCH.sub.2 Ph                                                                       sb                                     37       CH.sub.2 NHCH.sub.2 Ph                                                                       H              sb                                     38       CH.sub.2 P(O)(OCH.sub.2 Ph).sub.2                                                            H              sb                                     39       H              CH.sub.2 P(O)(OCH.sub.2 Ph).sub.2                                                            sb                                     40       CH.sub.2 P(O)(CH.sub.3).sub.2                                                                CH.sub.3       sb                                     41       CH.sub.3       CH.sub.2 P(O)(CH.sub.3).sub.2                                                                sb                                     ______________________________________                                         sb = single bond                                                              db = double bond                                                         

EXAMPLE 34 Preparation of Ammonium Salts of Compounds II

The lactone (1.0 mmol) from Example 1, Step 8, is dissolved withstirring in 0.1N NaOH (1.1 mmol) at ambient temperature. The resultingsolution is cooled and acidified by the dropwise addition of 1N HCl. Theresulting mixture is extracted with diethyl ether and the extract washedwith brine and dried (Mg SO₄). The MgSO₄ is removed by filtration andthe filtrate saturated with ammonia (gas) to give a gum which solidifiedto provide the ammonium salt.

EXAMPLE 35 Preparation of Alkali and Alkaline Earth Salts of CompoundsII

To a solution of 44 mg of lactone from Example 1, Step 8, in 2 ml ofethanol is added 1 ml of aqueous NaOH (1 equivalent). After one hour atroom temperature, the mixture is taken to dryness in vacuo to yield thedesired sodium salt.

In like manner, the potassium salt is prepared using one equivalent ofpotassium hydroxide, and the calcium salt, using one equivalent of CaO.

EXAMPLE 36 Preparation of Ethylenediamine Salts of Compounds II

To a solution of 0.50 g of the ammonium salt from Example 34 in 10 ml ofmethanol is added 0.04 ml of ethylenediamine. The methanol is strippedoff under vacuum to obtain the desired ethylenediamine salt.

EXAMPLE 37 Preparation of Tris(hydroxymethyl)aminomethane Salts ofCompounds II

To a solution of 202 mg of the ammonium salt from Example 34 in 5 ml ofmethanol is added a solution of 50 mg of tris(hydroxymethyl)aminomethane in 5 ml of methanol. The solvent is removed in vacuo toafford the desired tris(hydroxymethyl)aminomethane salt.

EXAMPLE 38 Preparation of L-Lysine Salts of Compounds II

A solution of 0.001 mole of L-lysine and 0.0011 mole of the ammoniumsalt from Example 34 in 15 ml of 85% ethanol is concentrated to drynessin vacuo to give the desired L-lysine salt.

Similarly prepared are the L-arginine, L-ornithine, andN-methylglucamine salts.

EXAMPLE 39 Preparation of Tetramethylammonium Salts of Compounds II

A mixture of 68 mg of ammonium salt from Example 34 in 2 ml of methylenechloride and 0.08 ml of 24% tetramethylammonium hydroxide in methanol isdiluted with ether to yield the desired tetramethylammonium salt.

EXAMPLE 40 Preparation of Methyl Esters of Compounds II

To a solution of 400 mg of lactone from Example 1, Step 8, in 100 ml ofabsolute methanol is added 10 ml 0.1M sodium methoxide in absolutemethanol. This solution is allowed to stand at room temperature for onehour, then is diluted with water and extracted twice with ethyl acetate.The organic phase is separated, dried (Na₂ SO₄), filtered and evaporatedin vacuo to yield the desired methyl ester.

In like manner, by the use of equivalent amounts of propanol, butanol,isobutanol, t-butanol, amylalcohol, isoamylalcohol,2,2-dimethylaminoethanol, benzylalcohol, phenethanol, 2-acetamidoethanoland the like, the corresponding esters are obtained.

EXAMPLE 41 Preparation of Free Dihydroxy Acids

The sodium salt of the compound II from Example 35 is dissolved in 2 mlof ethanol-water (1:1; v:v) and added to 10 ml of 1N hydrochloric acidfrom which the dihydroxy acid is extracted with ethyl acetate. Theorganic extract is washed once with water, dried (Na₂ SO₄), andevaporated in vacuo with a bath temperature not exceeding 30° C. Thedihydroxy acid derivative derived slowly reverts to the corresponding,parent lactone on standing. The compound can be maintained in thedihydroxy acid form by increasing the pH above 7.0.

EXAMPLE 42

As a specific embodiment of a composition of this invention, 20 mg oflactone from Example 1, Step 8, is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize 0, hard gelatin capsule.

What is claimed is:
 1. A compound represented by the following structural formulae (I) and (II): ##STR23## wherein: A is O or S(O)_(n) or N--R₁₃ ;n is 0 to 2; R₁ is selected from:(1) C₁₋₁₀ alkyl; (2) substituted C₁₋₁₀ alkyl in which one or more substitutent(s) is selected from(a) halogen, (b) hydroxy, (c) C₁₋₁₀ alkoxy, (d) C₁₋₅ alkoxycarbonyl, (e) C₁₋₅ acyloxy, (f) C₃₋₈ cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C₁₋₁₀ alkylS(O)_(n) in which n is 0 to 2, (j) C₃₋₈ cycloalkylS(O)_(n), (k) phenylS(O)_(n), (l) substituted phenylS(O)_(n) in which the substituents are X and Y, and (m) oxo; (3) C₁₋₁₀ alkoxy; (4) C₂₋₁₀ alkenyl; (5) C₃₋₈ cycloalkyl; (6) substituted C₃₋₈ cycloalkyl in which one substituent is selected from(a) C₁₋₁₀ alkyl, (b) substituted C₁₋₁₀ alkyl in which the substituent is selected from(i) halogen, (ii) hydroxy, (iii) C₁₋₁₀ alkoxy, (iv) C₁₋₅ alkoxycarbonyl, (v) C₁₋₅ acyloxy, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (viii) C₁₋₁₀ alkylS(O)_(n), (ix) C₃₋₈ cycloalkylS(O)_(n), (x) phenylS(O)_(n), (xi) substituted phenylS(O)_(n) in which the substituents are X and Y, and (xii) oxo, (c) C₁₋₁₀ alkylS(O)_(n), (d) C₃₋₈ cycloalkylS(O)_(n), (e) phenylS(O)_(n), (f) substituted phenylS(O)_(n) in which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) C₁₋₁₀ alkoxy, (j) C₁₋₅ alkoxycarbonyl, (k) C₁₋₅ acyloxy, (l) phenyl, and (m) substituted phenyl in which the substituents are X and Y; (7) phenyl; (8) substituted phenyl in which the substituents are X and Y; (9) amino; (10) C₁₋₅ alkylamino; (11) di(C₁₋₅ alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl C₁₋₁₀ alkylamino; (15) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are X and Y; (17) R₅ S in which R₅ is selected from(a) C₁₋₁₀ alkyl, (b) phenyl, and (c) substituted phenyl in which the substituents are X and Y; R₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₁₀ alkyl; and (3) substituted C₁₋₁₀ alkyl in which one or more substituents is selected from(a) halogen, (b) hydroxy, (c) C₁₋₁₀ alkoxy (d) C₁₋₅ alkoxycarbonyl, (e) C₁₋₅ alkylacyloxy, (f) phenylacyloxy, (g) phenoxycarbonyl, (h) phenyl C₁₋₅ alkylacyloxy, (i) phenyl C₁₋₅ alkyloxy, (j) amino, (k) C₁₋₅ alkylamino, (l) di(C₁₋₅ alkyl)amino, (m) phenylamino, (n) substituted phenylamino in which the substituents are X and Y; (o) phenyl C₁₋₅ alkylamino, (p) substituted phenyl C₁₋₅ alkylamino in which the substituents are X and Y, (q) C₃₋₈ cycloalkyl, (r) phenyl, (s) substituted phenyl in which the substituents are X and Y, (t) phenylS(O)_(n), (u) substituted phenyl S(O)_(n) in which the substituents are X and Y, (v) phenyl C₁₋₅ alkyl S(O)_(n), (w) C₁₋₅ alkylS(O)_(n) ; (x) phenylaminoacyloxy, (y) C₁₋₅ alkylaminoacyloxy, (z) C₁₋₅ alkylacylamino, (cc) phenylC₁₋₅ alkylacylamino; (4) R₂ and R₃ together with the carbon atom to which they are attached form a C₃₋₈ carbo-cyclic ring; R₄ is selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) substituted C₁₋₅ alkyl in which the substituent is selected from(a) phenyl, (b) dimethylamino, and (c) acetylamino, and (4) 2,3-dihydroxypropyl; R₁₃ is selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) substituted C₁₋₅ in which the substituent is selected from:(a) phenyl, (b) dimethylamino, and (c) acetylamino, and (d) hydroxy, provided that hydroxy is substituted only at C-2, C-3, C-4 or C-5; and (e) C₁₋₅ alkoxy; (4) C₁₋₅ alkylcarbonyl; (5) C₁₋₅ alkyloxycarbonyl; (6) C₁₋₅ alkylaminocarbonyl; X and Y independently are hydrogen, halogen, trifluoromethyl, C₁₋₃ alkyl, nitro, cyano or group selected from:(1) R₆ O(CH₂)_(m) in which m is 0 to 3 and R₆ is hydrogen, C₁₋₃ alkyl or hydroxy-C₂₋₃ alkyl; (2) ##STR24## in which R₇ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl, phenyl, naphthyl, amino-C₁₋₃ alkyl, C₁₋₃ alkylamino-C₁₋₃ alkyl, di(C₁₋₃ alkyl)amino-C₁₋₃ alkyl, hydroxy-C₂₋₃ alkylamino-C₁₋₃ alkyl or di(hydroxy-C₂₋₃ alkyl) amino-C₁₋₃ alkyl; provided that in ##STR25## R₇ is not H; (3) ##STR26## in which R₈ is hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, phenyl or naphthyl; (4) R₉ R₁₀ N(CH₂)_(m), ##STR27## in which R₉ and R₁₀ independently are hydrogen, C₁₋₃ alkyl, hydroxy-C₂₋₃ alkyl; (5) R₁₁ S(O)_(n) (CH₂)_(m) in which R₁₁ is hydrogen, C₁₋₃ alkyl, amino, C₁₋₃ alkylamino or di(C₁₋₃ alkyl)amino; a is a single bond or a double bond; halogen is F or Cl; or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 wherein:A is O or S(O)_(n) ; R₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₁₀ alkyl; (3) substituted C₁₋₁₀ alkyl in which one or more substituents is selected from:(a) halogen, (b) hydroxy, (c) amino; (4) CH2R₁₂ in which R₁₂ is selected from:(a) C₁₋₅ alkoxy, (b) C₁₋₅ alkoxycarbonyl, (c) C₁₋₅ alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylC₁₋₅ alkylacyloxy, (g) phenylC₁₋₅ alkoxy, (h) C₁₋₅ alkylamino, (i) di(C₁₋₅ alkyl)amino, (j) phenylamino, (k) substituted phenylamino in which the substituents are X and Y, (l) phenyl C₁₋₅ alkylamino, (m) substituted phenyl C₁₋₅ alkyl amino in which the substituents are X and Y, (n) C₃₋₈ cycloalkyl, (o) phenyl, (p) substituted phenyl in which the substituents are X and Y, (q) phenylS(O)_(n) (r) substituted phenylS(O)_(n) in which the substituents are X and Y, (s) phenyl C₁₋₅ alkylS(O)_(n), (t) C₁₋₅ alkylS(O)_(n), (u) phenylaminoacyloxy, (v) C₁₋₅ alkylaminoacyloxy, (w) C₁₋₅ alkylacylamino; (z) phenylC₁₋₅ alkylacylamino; (5) R₂ and R₃ together with the carbon atom to which they are attached from a C₃₋₈ carbocyclic ring.
 3. A compound of claim 2 wherein:R₁ is selected from:(1) C₁₋₁₀ alkyl; (2) substituted C₁₋₁₀ alkyl in which one or more substituent(s) is selected from(a) halogen, (b) hydroxy, (c) C₁₋₁₀ alkoxy, (d) C₁₋₅ alkoxycarbonyl, (e) C₁₋₅ acyloxy, (f) C₃₋₈ cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, and (i) oxo; (3) C₃₋₈ cycloalkyl; (4) substituted C₃₋₈ cycloalkyl in which one substituent is selected from(a) C₁₋₁₀ alkyl, (b) substituted C₁₋₁₀ alkyl in which the substituent is selected from(i) halogen, (ii) hydroxy, (iii) C₁₋₁₀ alkoxy, (iv) C₁₋₅ acyloxy, (v) C₁₋₅ alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) C₁₋₁₀ alkoxy, (f) C₁₋₅ alkoxycarbonyl, (g) C₁₋₅ acyloxy, (h) phenyl, (i) substituted phenyl in which the substituents ar X and Y; (5) phenylamino; (6) substituted phenylamino in which the substituents are X and Y; (7) phenyl C₁₋₁₀ alkylamino; and (8) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are X and Y.
 4. A compound of claim 3 wherein:R₁ is selected from:(1) C₁₋₁₀ alkyl; (2) C₃₋₈ cycloalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y.
 5. A compound of claim 4 wherein:R₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) C₁₋₅ alkyl substituted with hydroxy; (4) CH₂ R₁₂ in which R₁₂ is selected from:(a) C₁₋₅ alkoxy, (b) C₁₋₅ alkoxycarbonyl, (c) C₁₋₅ alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylC₁₋₅ alkylacyloxy. (g) phenylC₁₋₅ alkoxy, (h) phenyl S(O)_(n), (i) substituted phenyl S(O)_(n) in which the substituents are X and Y, (j) phenylC₁₋₅ alkyl S(O)_(n), (k) C₁₋₅ alkyl S(O)_(n), (l) phenylaminoacyloxy, (m) C₁₋₅ alkylaminoacyloxy, (n) phenyl, (o) substituted phenyl in which the substituents are X and Y; (p) C₁₋₅ alkylacylamino; (q) phenylC₁₋₅ alkylacylamino.
 6. A compound of claim 5 wherein:R₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) C₁₋₅ substituted with hydroxy; (4) CH₂ R₁₂ in which R₁₂ is selected from:(a) C₁₋₅ alkoxy, (b) phenyl S(O)_(n), (c) phenylC₁₋₅ alkyl S(O)_(n), (d) phenylaminoacyloxy, (e) C₁₋₅ alkylacylamino, (f) phenylC₁₋₅ alkylacylamino.
 7. A compound of claim 6 wherein:R₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) C₁₋₅ alkyl substituted with hydroxy; (4) phenyl S(O)_(n) CH₂.
 8. A compound of claim 7 wherein:A is O; a is a single bond; and R₁ is 2-methyl-2-butyl or 2-butyl; and R₂ and R₃ are independently selected from CH₃, H, phenylthiomethyl and hydroxymethyl.
 9. A compound of claim 8 selected from:(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyrloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R) hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (5) 6(R)-[2 [8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5- oxa-6(S)-(hydroxymethyl, methyl)-1,2,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy) 2(S)-methyl-5-oxa-6(R)-(hydroxymethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (7) 6(R)- [2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5 oxa-6(S)-(phenylthiomethyl, hydroxy methyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pryan-2-one; (8)6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, hydroxymethyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;and the corresponding ring opened dihydroxy acids and esters thereof.
 10. A compound of claim 9 which is:(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy 3,4,5,6-tetrahydro-2H-pyran-2-one;and the corresponding ring opened dihydroxy acids and esters thereof.
 11. A compound of claim 7 wherein:A is S(O)_(n) ; a is a single bond; and R₁ is 2-methyl-2-butyl or 2-butyl; and R₂ and R₃ are independently selected from CH₃, H and hydroxymethyl.
 12. A compound of claim 1 wherein:A is N--R₁₃ ; and R₁ is selected from:(1) C₁₋₁₀ alkyl; (2) substituted C₁₋₁₀ alkyl in which one or more substituents(s) is selected from(a) halogen, (b) hydroxy, (c) C₁₋₁₀ alkoxy, (d) C₁₋₅ alkoxycarbonyl, (e) C₁₋₅ acyloxy, (f) C₃₋₈ cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, and (i) oxo; (3) C₃₋₈ cycloalkyl; (4) substituted C₃₋₈ cycloalkyl in which one substituent is selected from(a) C₁₋₁₀ alkyl, (b) substituted C₁₋₁₀ alkyl in which the substituent is selected from(i) halogen, (ii) hydroxy, (iii) C₁₋₁₀ alkoxy (iv) C₁₋₅ acyloxy, (v) C₁₋₅ alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) C₁₋₁₀ alkoxy, (f) C₁₋₅ alkoxycarbonyl, (g) C₁₋₅ acyloxy, (h) phenyl, (i) substituted phenyl in which the substituents are X and Y; (5) phenylamino; (6) substituted phenylamino in which the substituents are X and Y; (7) phenylC₁₋₁₀ alkylamino; and (8) substituted phenyl C₁₋₁₀ alkylamino in which the substituents are X and Y; R₂ and R₃ are independently selected from(1) hydrogen; (2) C₁₋₁₀ alkyl; (3) substituted C₁₋₁₀ alkyl in which one or more substituents is selected from:(a) halogen, (b) hydroxy, (c) amino; (4) CH₂ R₁₂ in which R₁₂ is selected from:(a) C₁₋₅ alkoxy, (b) C₁₋₅ alkoxycarbonyl, (c) C₁₋₅ alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylC₁₋₅ alkylacyloxy, (g) phenylC₁₋₅ alkoxy, (h) C₁₋₅ alkylamino, (i) di(C₁₋₅ alkylamino), (j) phenylamino, (k) substituted phenylamino in which the substituents are X and Y, (l) phenyl C₁₋₅ alkylamino, (m) substituted phenyl C₁₋₅ alkyl amino in which the substituents are X and Y, (n) C₃₋₈ cycloalkyl, (o) phenyl, (p) substituted phenyl in which the substituents are X and Y, (q) phenylS(O)_(n) (r) substituted phenylS(O)_(n) in which the substituents are X and Y, (s) phenyl C₁₋₅ alkylS(O)_(n), (t) C₁₋₅ alkylS(O)_(n), (u) phenylaminoacyloxy, (v) C₁₋₅ alkylaminoacyloxy, (w) C₁₋₅ alkylacylamino, (5) R₂ and R₃ together with the carbon atom to which they are attached form a C₃₋₈ carbocyclic ring.
 13. A compound of claim 12 wherein:R₁ is selected from:(1) C₁₋₁₀ alkyl; (2) C₃₋₈ cylcoalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y; R₁₃ is selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) phenylC₁₋₅ alkyl; (4) C₁₋₅ alkylcarbonyl.
 14. A compound of claim 13 whereinR₂ and R₃ are independently selected from:(1) hydrogen; (2) C₁₋₅ alkyl; (3) C₁₋₅ alkyl substituted with hydroxy; (4) CH₂ R₁₂ in which R₁₂ is selected from:(a) C₁₋₅ alkoxy, (b) C₁₋₅ alkoxycarbonyl, (c) C₁₋₅ alkylacyloxy, (d) phenylacyloxy, (e) phenoxycarbonyl, (f) phenylC₁₋₅ alkylacyloxy, (g) phenylC₁₋₅ alkoxy, (h) phenyl S(O)_(n), (i) substituted phenyl S(O)_(n) in which the substituents are X and Y, (j) phenylalkyl S(O)_(n), (k) C₁₋₅ alkyl S(O)_(n), (l) phenylaminoacyloxy, (m) C₁₋₅ alkylaminoacyloxy, (n) phenyl, (o) substituted phenyl in which the substituents are X and Y.
 15. A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as defined in claim
 1. 16. A composition of claim 15 in which the compound is selected from:(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6 -tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R) octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6 -tetrahydro-2H-pyran-2-one; (3) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(hydroxymethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (7) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, hydroxymethyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (8) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, hydroxymethyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; and the corresponding ring opened dihydroxy acids and esters thereof.
 17. A method of inhibiting cholesterol biosynthesis comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim
 1. 18. A method of claim 17 in which the compound is selected from:(1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (3)-6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (4) 6(R)-[2-[8(S)-(2-methylbutyryloxy)-2(S)-methyl-5-oxa-6,6-dimethyl-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (5) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(hydroxymethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (6) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(hydroxymethyl, methyl)-1,2,3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)] ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (7) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(S)-(phenylthiomethyl, hydroxymethyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (8) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-5-oxa-6(R)-(phenylthiomethyl, hydroxymethyl)-1,2,-3,4,4a(R),7,8,8a(R)-octahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; and the corresponding ring opened dihydroxy acids and esters thereof. 